A new strategy that targets two distinct pathways through which antibodies cause hypersensitivity has shown promise for treating severe allergies, a study suggests.
The combination approach targets the production of Immunoglobulin E—a key driver of type 1 hypersensitivity and allergies—while maintaining regular immune responses.
The tactic acts not only upon IgE generation by B cells but also its production through long-lived plasma cells (PCs), which retain allergic “memory” long after allergen exposure.
“These findings suggest that long-lived IgE+ PCs are an important source of IgE memory and allergy, which are not targeted by existing therapeutic approaches,” report Andre Limnander and colleagues at Regeneron Pharmaceuticals in the journal Science Translational Medicine.
Allergic disorders continue to rise worldwide, with an estimated one in 10 people having some form of food allergy in the U.S. alone.
No current therapies are yet able to fully prevent the IgE production, with the added complication that any treatment would need to maintain the immune system’s normal antibody-producing capabilities.
In the current study, Limnander et al. examined whether it would be possible to reset allergic responses by eliminate existing IgE-producing plasma cells and prevent new ones from forming.
Firstly, they first temporarily removed all plasma cells—including the IgE producing cells—using a bispecific antibody against B-cell maturation antigen (BCMA) and CD3.
The team then deployed the antibody monoclonal antibody dupilumab, which blocks the interleukin-4 receptor (IL-4R)α needed to generate IgE-producing plasma cells. IL4R blockade prevented further de novo class switching to IgE from the memory B cells to re-constitute the depleted plasma cell pool.
The two-step approach completely prevented the reemergence of IgE when combined with the IL-4Rα blocker while allowing non–IgE-producing plasma cells to repopulate quickly, reestablishing production of other immunoglobulin classes.
Combination treatment was able to prevent anaphylaxis in mice sensitized to dust mites and durably depleted IgE in macaque monkeys.
The researchers also found that weekly use of the BCMAxCD3 bispecific antibody in patients with multiple myeloma reduced IgE concentrations as early as 4 weeks after treatment.
They conclude: “The combination approach, which we describe, involving transient PC ablation combined with persistent IL-4Rα blockade represents an attractive near-term clinical strategy that may hold great promise for a human trial.”
